Transportation of market-weight pigs: I. effect of season, truck type, and location within truck on behavior with a two-hour transport.
There is evidence that season and truck/trailer design play important roles in pig welfare during transportation although little is known about their interaction and effect on pig behavior. This experiment was designed to examine the influence of season and truck/trailer design on the behavior during loading, transit, unloading, and lairage of market-weight pigs transported to slaughter. A total of 3,756 pigs were transported on either a 3-deck pot-belly trailer (PB; n = 181 pigs/wk in 8 experimental compartments) or a double-decker hydraulic truck (DD; n = 85 pigs/wk in 4 compartments) for 2 h to a commercial abattoir in summer and winter (6 wk in each season). Density on both vehicles was 0.40 m(2)/pig. Accounting for the number of pigs, loading took longer (P = 0.033) onto the DD than the PB, but season did not (P = 0.571) influence loading time. Pigs loaded onto the PB moved backward more (P = 0.003) frequently than those loaded onto the DD. The frequency of tapping by handler was the lone handling intervention affected by truck type, with more (P = 0.014) tapping needed to move pigs on and off DD than PB. During loading, pigs made more (P < 0.001) slips and falls, overlaps, 180° turns, underlaps, and vocalizations in winter compared with summer. On truck, more (P < 0.001) pigs were standing on the DD at the farm and in transit than on the PB whereas more (P = 0.012) pigs were lying in transit in summer than in winter. Pigs took longer to unload (P < 0.001) from the PB than the DD, but no difference between vehicles (P = 0.473) in latency to rest in lairage was found. Pigs slipped and fell more (P < 0.001) during unloading, took longer (P < 0.001) to unload, and had a shorter (P = 0.006) latency to rest in lairage in winter than summer. Vehicle design, in particular the presence of ramps, influenced pig behavior before, during, and after transportation, regardless of the season. Season affected loading and unloading behavior, especially in terms of slips and falls on the ramp, and differences in truck/trailer designs were also partly to blame for unloading times and lairage behavior. Ramps and changes in direction during unloading appear to slow down the handling process.


Extragenital malignant transmissible venereal tumour in a bitch.
Transmissible venereal tumor was diagnosed in the vagina of a bitch. The tumor spread to the oral mucosa in the tonsilar area of a female offspring which was frequently observed licking the vaginal discharge from the bitch. Metastasis to the ovary occurred in the bitch and wide-spread metastasis, especially to the skin, lymph nodes and spleen was recorded in the offspring. Both animals were euthanased due to poor response to treatment. The diagnoses were confirmed by histopathological examination.


Efficiency of weight gain of serial slaughtered bulls of a five-breed diallel.
Weight and feed consumption of 197 bulls were recorded monthly in a serial slaughter experiment continuing over a period of 24 mo. The bulls were produced in a modified five-breed diallel of the Angus, Brahman, Hereford, Holstein and Jersey breeds. Our objective was to estimate efficiency of feed conversion for weight gain for each breed and cross. The model included average weight gain per day (ADG) as a dependent variable; independent variables included breed-type, season, month within season, average feed intake per day (ADI), initial weight, weight to the .75 power, breed x ADI and season x ADI effects. The sum of the partial regression coefficients of ADG on ADI and on breed x ADI adjusted for season, month within season, initial weight, weight to the .75 power and season x ADI was interpreted to be an estimate of intrinsic or net efficiency of ADG. There were no significant differences among the various breed-types in intrinsic efficiency of ADG. Average heterosis for intrinsic efficiency of feed conversion was not significant. None of the contrasts among breed-types was significant for intrinsic efficiency of ADG (British vs dairy, 1.1 +/- 12.3 g/d; Brahman-dairy crosses vs British-dairy crosses, 32.7 +/- 12.9 g/d; British-Brahman crosses vs British-dairy crosses, 13.9 +/- 12.4 g/d; British-Brahman crosses vs straightbred British 3.2 +/- 14.8 g/d).


Evaluating the efficacy of remediation for struggling readers in high school.
Preliminary efficacy data are reported for a research-based reading intervention designed for struggling readers in high school. PHAST PACES teaches (a) word identification strategies, (b) knowledge of text structures, and (c) reading comprehension strategies. In a quasi-experimental design, 268 intervention and 83 waiting list control students meeting criteria for reading disability were assessed before and after their semester. After 60 to 70 hours of PHAST PACES instruction, struggling readers demonstrated significant gains on standardized tests of word attack, word reading, and passage comprehension and on experimental measures of letter-sound knowledge and multisyllabic word identification relative to control students. An average effect size of .68 was revealed across these outcome measures. One year follow-up data on 197 PHAST PACES students revealed an average trend to decelerated growth after the intervention, except for passage comprehension outcomes that demonstrated continued growth over follow-up.


School-Based Interventions to Promote Empathy-Related Responding in Children and Adolescents: A Developmental Analysis.
Empathy has been identified as a core component of social and emotional functioning across development. Various prevention and intervention programs have utilized components of empathy-related responding to promote the development of children's and adolescents' social-emotional functioning and impede their aggression in school contexts. In this article, we assess the effectiveness of select school-based empathy interventions and the extent to which they align with developmental theory and research. First, we review current conceptualizations of empathy-related responding, identify its components, outline its normative development, and describe the need for developmentally tailored interventions. We then identify and assess the effectiveness and developmental sensitivity of 19 school-based programs with strong empirical support that target empathy-related responding across childhood and adolescence. Although the majority of these programs showed some degree of developmental differentiation between grades, none considered developmental differences within grades. Commencing interventions earlier in development and targeting higher numbers of empathy-related constructs were, in part, associated with larger effects. We discuss how future research can bridge the gap between basic developmental research and the design of developmentally tailored interventions to promote empathy-related responding.


Strength training reduces freely chosen pedal rate during submaximal cycling.
The freely chosen pedal rate is relatively high and energetically inefficient during submaximal cycling, which is a paradox since the rate of energy expenditure is considered important for voluntary motor behavior in other cyclical activities as, e.g., running. For example, it has been suggested that subjects pedal fast to reduce the perception of force. In this study, we investigated the hypothesis that strength training would cause subjects to pedal at a slower rate during low to moderate submaximal cycling. Fourteen healthy subjects performed supervised heavy (2-12 RM) strength training 4 days/week for 12 weeks, including 2 days/week with leg-extensor and knee-flexor exercises. Seven healthy subjects formed the control group. The training group increased strength (one repetition maximum, 1 RM) in both squat [20%(3), mean (SEM)] and leg curl [12%(1)] exercises from the beginning to the end of the study period (p<0.01). At the same time, freely chosen pedal rate was reduced by 8 (2) and 10 (2) rpm, respectively, during cycling at 37 and 57% of maximal power output (Wmax) (p<0.01). In addition, rate of energy expenditure is 3% (2) lower at 37% of Wmax (p<0.05) and tended to be lower at 57% Wmax (p=0.07) at the end of the study. Values for strength, freely chosen pedal rate, and rate of energy expenditure, were unchanged for the control group from the beginning to the end of the study. In conclusion, strength training caused subjects to choose an approximately 9 rpm lower pedal rate during submaximal cycling. This was accompanied by a approximately 3% lower rate of energy expenditure.


Real-Time Surface Plasmon Resonance (SPR) for the Analysis of Interactions Between SUMO Traps and Mono- or PolySUMO Moieties.
Isolating endogenous SUMOylated proteins is a challenging task due to the high reversibility of this posttranslational modification. We have shown that SUMO traps are useful tools for the enrichment and isolation of proteins modified by SUMO in vitro and in vivo. To characterize the affinity and specificity of different SUMO chains for these traps, that are based on SUMO-interacting motifs, we have used real-time surface plasmon resonance (SPR), which allows a label-free analysis of protein/protein interactions. Here, a protocol to determine the affinities of multivalent SUMO traps for polySUMO chains or mono-SUMO molecules by SPR is presented.


Optic nerve involvement in the acute retinal necrosis syndrome.
Two patients with acute retinal necrosis syndrome demonstrated enlarged computed tomographic images of the optic nerves, a previously undescribed manifestation of this disorder to the best of our knowledge. One patient, with the bilateral variety of this syndrome, demonstrated bilateral optic nerve enlargement and, in one eye, appeared to achieve visual improvement following an optic nerve sheath decompression. The second patient, with the unilateral variety of the syndrome, demonstrated only unilateral optic nerve enlargement. These observations suggest that the intraorbital optic nerve may be primarily or secondarily involved in the acute retinal necrosis syndrome.


Primary amino-bisphosphonates: a new class of gastrotoxic drugs--comparison of alendronate and aspirin.
Alendronate and pamidronate are primary amino-bisphosphonates used in the treatment of metabolic bone disease. Both drugs have been associated with reversible erosive esophagitis and as a result pamidronate is approved in the United States only for parenteral use. In rats, alendronate causes acute gastric mucosal damage similar to that seen with aspirin or nonsteroidal anti-inflammatory drugs. We performed a blinded, crossover, randomized, single-center, placebo-controlled, endoscopic comparison of alendronate (40 mg/day), aspirin (1, 300 mg/day), and placebo to evaluate the presence and degree of mucosal damage to the esophagus, stomach, and duodenal bulb. Twelve normal healthy volunteers were studied both before and after 4 days of drug therapy. Placebo caused no visible endoscopic damage. In contrast, both aspirin and alendronate were associated with visible gastric mucosal injury in the majority of those studied (75 and 58%, respectively) and both were significantly greater than placebo (p < 0.001). The gastric mucosal injury was deemed severe in 50% of those receiving alendronate or aspirin; one alendronate-associated gastric ulcer was seen. Esophageal and duodenal bulb injury was seen once each, and both were associated with alendronate. The primary amino-bisphosphonate alendronate causes mucosal injury to the upper gastrointestinal tract similar to aspirin. Even when used according to manufacturer's dosing instructions alendronate should probably be used with caution.


The KMT1A-GATA3-STAT3 Circuit Is a Novel Self-Renewal Signaling of Human Bladder Cancer Stem Cells.
Purpose: Bladder cancer is one of the most common urinary malignancies worldwide characterized by a high rate of recurrence and no targeted therapy method. Bladder cancer stem cells (BCSCs) play a crucial role in tumor initiation, metastasis, and drug resistance. However, the regulatory signaling and self-renewal mechanisms of BCSCs remain largely unknown. Here, we identified a novel signal, the KMT1A-GATA3-STAT3 circuit, which promoted the self-renewal and tumorigenicity of human BCSCs.Experimental Design: In a discovery step, human BCSCs and bladder cancer non-stem cells (BCNSCs) isolated from primary bladder cancer samples #1 and #2, and the bladder cancer cell line EJ were analyzed by transcriptome microarray. In a validation step, 10 paired bladder cancer and normal tissues, different tumor cell lines, the public microarray datasets of human bladder cancer, and The Cancer Genome Atlas database were applied for the verification of gene expression.Results: KMT1A was highly expressed and responsible for the increase of tri-methylating lysine 9 of histone H3 (H3K9me3) modification in BCSCs compared with either BCNSCs or normal bladder tissue. GATA3 bound to the -1710∼-1530 region of STAT3 promoter and repressed its transcription. H3K9me3 modification on the -1351∼-1172bp region of the GATA3 promoter mediated by KMT1A repressed the transcription of GATA3 and upregulated the expression of STAT3. In addition, the activated STAT3 triggered self-renewal of BCSCs. Furthermore, depletion of KMT1A or STAT3 abrogated the formation of BCSC tumorspheres and xenograft tumors.Conclusions: KMT1A positively regulated the self-renewal and tumorigenicity of human BCSCs via KMT1A-GATA3-STAT3 circuit, in which KMT1A could be a promising target for bladder cancer therapy. Clin Cancer Res; 23(21); 6673-85. ©2017 AACR.


Interpretation of the Fractional Excretion of Sodium in the Absence of Acute Kidney Injury: A Cross-Sectional Study.
The fractional excretion of sodium (FeNa) may be helpful in establishing the cause of acute renal failure. This study was performed to determine the influence of the glomerular filtration rate (GFR), sodium intake, and tubular function on FeNa in children without renal failure. In this single institute cross-sectional study, 24-h-urine collections from patients (4-18 years of age, GFR >60 mL/min/1.73 m2) were used when considered reliable, and analyzed to determine sodium excretion, creatinine clearance and FeNa. The influence of tubular function was studied in 5 patients with generalized tubular dysfunction. Based on data from 761 patients, a multiple regression formula was designed based on GFR and sodium excretion that predicted over 80% of the variation in FeNa (R2 = 0.824, p < 0.001). Using this formula, the predicted FeNa was significantly lower than the measured FeNa in the children with tubular dysfunction. FeNa depends on GFR and sodium intake, and tubular function cannot be assessed without possessing adequate knowledge on all factors. Therefore, no normal range or cut-off value for FeNa to assess tubular function can be given, and doing so is a misapplication of this equation.


Effect of surface roughness and stainless steel finish on Listeria monocytogenes attachment and biofilm formation.
The purpose of this study was to evaluate the effect of surface roughness (Ra) and finish of mechanically polished stainless steel (Ra = 0.26 +/- 0.05, 0.49 +/- 0.10, and 0.69 +/- 0.05 microm) and electropolished stainless steel (Ra = 0.16 +/- 0.06, 0.40 +/- 0.003, and 0.67 +/- 0.02 microm) on Listeria adhesion and biofilm formation. A four-strain cocktail of Listeria monocytogenes was used. Each strain (0.1%) was added to 200 ml of tryptic soy broth (TSB), and coupons were inserted to the mixture for 5 min. For biofilm formation, coupons with adhesive cells were incubated in 1:20 diluted TSB at 32 degrees C for 48 h. The experiment was performed by a randomized block design. Our results show that the level of Listeria present after 48 h of incubation (mean = 7 log CFU/cm2) was significantly higher than after 5 min (mean = 6.0 log CFU/cm2) (P < 0.01). No differences in initial adhesion were seen in mechanically finished (mean = 6.7 log CFU/cm2) when compared with electropolished stainless steel (mean = 6.7 log CFU/cm2) (P > 0.05). Listeria initial adhesion (values ranged from 5.9 to 6.1 log CFU/cm2) or biofilm formation (values ranged from 6.9 to 7.2 log CFU/cm2) was not significantly correlated with Ra values (P > 0.05). Image analysis with an atomic force microscope showed that bacteria did not colonize the complete surface after 48 h but were individual cells or grouped in microcolonies that ranged from 5 to 10 microm in diameter and one to three cell layers in thickness. Exopolymeric substances were observed to be associated with the colonies. According to our results, electropolishing stainless steel does not pose a significant advantage for food sanitation over mechanically finished stainless steel.


Advanced virtual endoscopic pituitary surgery.
Endoscopy has recently been introduced to endonasal transsphenoidal pituitary surgery as a minimally invasive procedure for the removal of various kinds of pituitary tumors. To reduce morbidity and mortality with this new technique, the surgeon must be well-trained and well-prepared. Virtual endoscopy can be beneficial as a tool for training, preoperative planning, and intraoperative support. This paper introduces STEPS, a virtual endoscopy system designed to aid surgeons in getting acquainted with the endoscopic view of the anatomy, the handling of instruments, the transsphenoidal approach, and challenges associated with the procedure. STEPS also assists experienced surgeons in planning a real endoscopic intervention by getting familiar with the individual patient anatomy, identifying landmarks, planning the approach, and deciding upon the ideal target position of the actual surgical activity. The application provides interactive visualization, navigation, and perception aids and the possibility of simulating the procedure, including haptic feedback and simulation of surgical instruments.


Learning through Osmosis: A global Wikipedia editing course for medical students.
This article was migrated. The article was marked as recommended. Problem: Wikipedia is a ubiquitous source of information for patients, medical students and junior doctors alike. This is despite medical educators discouraging students from Wikipedia as a source of medical information. Intervention: To address this disconnect, Osmosis' Director of Open Learning Initiatives created a novel Wikipedia-editing course structured to leverage the global network of Osmosis-subscribing students. The course was entirely video-conference based and lasted 4 weeks in July 2019. Students typically worked on an article by themselves though one article was selected by two students. Towards the end of the course, each student peer-reviewed another student's edited article. Outcomes:Twelve medical students, from 11 different medical schools across 3 different continents, enrolled in the course and 11 articles were assigned. A total of 8,775 words and 119 higher quality references were added whilst 35 lower-quality references were removed. An exit survey showed students had increased confidence in their ability to contribute to Wikipedia. Students also enjoyed collaborating with a global diversity of peers. Lessons Learned: Numerous students wished that the course had a longer duration. A couple students recommended more groupwork to be incorporated into the course. The global nature of the course meant that time zones proved a challenge to scheduling. Conclusion:Decentralized courses can leverage the large user bases of medical education companies, such as Osmosis, to teach students analytical approaches to online resources as well as improve the quality of publicly available health information on Wikipedia.


Role of the N-terminal region of ribosomal protein S7 in its interaction with 16S rRNA which binds to the concavity formed by the beta-ribbon arm and the alpha-helix.
The ribosomal protein S7, a primary 16S rRNA-binding protein, plays an essential role in stabilizing the 3' major domain of 16S rRNA and also in feedback regulation of the str operon, as a translational repressor. We examined amino acid residues in ribosomal protein S7 from Bacillus stearothermophilus (BstS7) that are essential for 16S rRNA binding. Truncation of the N-terminal 10 residues of BstS7 abolished its binding to 16S rRNA, whereas removal of the C-terminal eight residues had no effect on the binding activity. Subsequently, we used site-directed mutagenesis to identify essential basic residues in the N-terminal region for 16S rRNA binding. Mutation of Arg3 and Lys8 significantly weakened the binding activity, and a smaller decrease in binding activity was observed with Arg2 and Arg9 mutations. These observations indicate that N-terminal basic residues, especially Arg3 and Lys8, play a crucial role as positively charged recognition groups for the negatively charged phosphate backbone of 16S rRNA. In addition, the mutagenesis study showed that Arg75, Arg78, Arg94, and Arg101, which are located in a concavity formed by the beta-ribbon arm and the alpha-helix (alpha4), individually make only a small contribution to 16S rRNA binding, but together probably form a positively charged binding site for 16S rRNA. With regard to aromatic residues, Tyr84 on the tip of the beta-ribbon arm was found to be involved in 16S rRNA binding, whereas the conserved aromatic residues Trp102 and Tyr106 in the concavity had little effect. We then probed the 16S rRNA-binding site(s) for the N-terminal region of S7 with iron tethered to the mutant of BstS7 containing a single cysteine residue at position 4. The N-terminal region of S7 is placed in close proximity to helix 43 in the 16S rRNA. Probing also revealed additional cleavages between nucleotides 1397 and 1438, near the P-site region in 16S rRNA. This finding is consistent with a three-dimensional model of 16S rRNA that shows close proximity of helix 43 to the P-site during three-dimensional folding.


Expanding Eligibility Criteria for Nipple-Sparing Mastectomy.
The use of mastectomy has increased in patients who are high-risk genetic carriers who need or desire mastectomy for prophylactic reasons, as well as for patients who have breast cancer and need or desire mastectomy for treatment of their cancer. Retaining the nipple and skin with a nipple-sparing mastectomy results in improved patient satisfaction as compared with traditional mastectomy, without compromise of oncologic principles. This technique has been performed in patients with small, peripherally located tumors and nonptotic breasts; in recent years, however, consideration has been given to patients with more centrally located, larger tumors, and patients undergoing radiation or with ptotic breasts with the potential for poor cosmetic outcome. As the use of nipple-sparing mastectomy increases, it is important to continually assess the eligibility of patients for this technique.


Selectivity of McN-A-343 in stimulating phosphoinositide hydrolysis mediated by M1 muscarinic receptors.
The potency and efficacy of McN-A-343 (McN) in stimulating phosphoinositide (PI) hydrolysis were investigated in Chinese hamster ovary cells transfected with the m1 and m3 muscarinic receptor genes, in comparison with carbamylcholine (CBC). In m1 cells, CBC and McN increased PI hydrolysis by 17- and 9-fold over basal, respectively, with corresponding EC50 values of 4.2 and 4.3 microM. Whereas the maximal stimulatory response to CBC was slightly less in m3 cells (11-fold over basal), McN elicited only up to a 2-fold increase in PI hydrolysis in these cells. Competition binding data with N-[3H]methylscopolamine showed that McN had a higher affinity in m1 than in m3 cells, whereas CBC did not differentiate well between the two receptor subtypes. The partial agonistic activity of McN was demonstrated by its ability to suppress the stimulation by CBC to its own maximal response in both cell lines in a dose-dependent manner and by its low efficacy and the absence of receptor spareness. The PI response to the full agonist CBC in m3 cells was associated with a larger receptor reserve than in m1 cells. Thus, differences in receptor spareness cannot account for the apparent selectivity of McN in activating m1 muscarinic receptors. Differences in the sensitivity of m1 and m3 cells to McN were not due to differences in receptor concentration, despite the fact that the receptor density in m1 cells was 2-fold higher than in m3 cells. Our results suggest an actual selectivity (but not necessarily specificity) of the effects of McN in increasing Pl hydrolysis mediated by M1 receptors.


Novel arrhythmogenic mechanism revealed by a long-QT syndrome mutation in the cardiac Na(+) channel.
Variant 3 of the congenital long-QT syndrome (LQTS-3) is caused by mutations in the gene encoding the alpha subunit of the cardiac Na(+) channel. In the present study, we report a novel LQTS-3 mutation, E1295K (EK), and describe its functional consequences when expressed in HEK293 cells. The clinical phenotype of the proband indicated QT interval prolongation in the absence of T-wave morphological abnormalities and a steep QT/R-R relationship, consistent with an LQTS-3 lesion. However, biophysical analysis of mutant channels indicates that the EK mutation changes channel activity in a manner that is distinct from previously investigated LQTS-3 mutations. The EK mutation causes significant positive shifts in the half-maximal voltage (V(1/2)) of steady-state inactivation and activation (+5.2 and +3.4 mV, respectively). These gating changes shift the window of voltages over which Na(+) channels do not completely inactivate without altering the magnitude of these currents. The change in voltage dependence of window currents suggests that this alteration in the voltage dependence of Na(+) channel gating may cause marked changes in action potential duration because of the unique voltage-dependent rectifying properties of cardiac K(+) channels that underlie the plateau and terminal repolarization phases of the action potential. Na(+) channel window current is likely to have a greater effect on net membrane current at more positive potentials (EK channels) where total K(+) channel conductance is low than at more negative potentials (wild-type channels), where total K(+) channel conductance is high. These findings suggest a fundamentally distinct mechanism of arrhythmogenesis for congenital LQTS-3.


Graves' disease with spontaneous resolution following ocrelizumab in primary progressive multiple sclerosis.
Objectives. Immune reconstitution therapies (IRT), which include antibody-based cell-depleting therapies targeting CD52+ (alemtuzumab) or CD20+ (rituximab, ocrelizumab) leukocytes, are approved for the treatment of multiple sclerosis. Thyroid autoimmunity is a common adverse effect of alemtuzumab treatment, Graves' disease (GD) being the most prevalent manifestation. To date, thyroid autoimmunity events have not been reported with CD20-targeting monoclonal antibodies. Case Report. A 59-year-old woman with primary progressive multiple sclerosis with no prior personal history of thyroid disease or autoimmunity, was diagnosed with GD 6 months following the first ocrelizumab infusion. She was asymptomatic and had no signs of ophthalmopathy. Due to the temporal association of GD diagnosis with ocrelizumab infusion, absence of symptoms and our experience with alemtuzumab-induced GD, we decided for an active surveillance strategy and antithyroid drugs were not started. She underwent spontaneous resolution of hyperthyroidism with thyroid-stimulating hormone (TSH) receptor antibodies (TRAb) negativity and a mild and transitory period of subclinical hypothyroidism, while she continued the biannually ocrelizumab administration schedule. To present date, she has maintained close clinical and biochemical surveillance with normal TSH, free thyroxine (fT4) and free triiodothyronine (fT3) levels and undetectable TRAb. Conclusions. This is the first case of GD reported after ocrelizumab administration. The timing, onset and course of this case is similar to alemtuzumab-induced GD, usually interpreted as an "immune reconstitution syndrome"; however, ocrelizumab cell count depletion is inferior in severity, cell population affected and duration of depletion. This case highlights the importance of pre-screening and follow-up with thyroid function tests in patients treated with ocrelizumab. As a novel therapeutic antibody, further investigation is required to unravel the causes of thyroid autoimmunity.


Hutchinson-Gilford progeria syndrome through the lens of transcription.
Lamins are nuclear intermediate filaments. In addition to their structural roles, they are implicated in basic nuclear functions such as chromatin organization, DNA replication, transcription, DNA repair, and cell-cycle progression. Mutations in human LMNA gene cause several diseases termed laminopathies. One of the laminopathic diseases is Hutchinson-Gilford progeria syndrome (HGPS), which is caused by a spontaneous mutation and characterized by premature aging. HGPS phenotypes share certain similarities with several apparently comparable medical conditions, such as aging and atherosclerosis, with the conspicuous absence of neuronal degeneration and cancer rarity during the short lifespan of the patients. Cell lines from HGPS patients are characterized by multiple nuclear defects, which include abnormal morphology, altered histone modification patterns, and increased DNA damage. These cell lines provide insight into the molecular pathways including senescence that require lamins A and B1. Here, we review recent data on HGPS phenotypes through the lens of transcriptional deregulation caused by lack of functional lamin A, progerin accumulation, and lamin B1 silencing.


Ankylosing spondylitis is characterized by an increased turnover of several different metalloproteinase-derived collagen species: a cross-sectional study.
Ankylosing spondylitis (AS) is characterized by gradual cementation of the vertebrae, a process that is described by excessive extracellular matrix remodeling. Specific matrix metalloproteinase (MMP)-derived collagen fragments are released to the circulation, and measurement of those might act as biomarkers of ankylosis. The aim of the study was to investigate the diagnostic value of five novel assays measuring different collagen species. Five newly developed ELISAs measuring MMP-degraded collagen fragments in serum of 40 AS patients and 40 age-matched controls were measured: collagen type I (C1M), type II (C2M), type III (C3M), type IV (C4M) and type VI (C6M) as well as the bone formation marker osteocalcin. The levels of the five collagen neoepitopes were significantly higher in AS patients, except for osteocalcin. Cartilage degradation (C2M) was only significantly correlated with the basement membrane (C4M) in the AS patients. In contrast, C3M was significantly correlated with all of the other collagen markers. The highest diagnostic value was achieved when combining the C2M, C3M and C6M markers, AUC 87% (P < 0.0001). Moreover, a combination of the markers correlated with the clinical mSASS score (P = 0.004, R = 0.44). Novel and unique biomarkers of tissue remodeling may provide diagnostic value and aid in understanding of the AS pathology. Each of the biomarkers tells a unique story, and by combining them in a panel there, we found a strong correlation with mSASSS. We speculate that such panel will be a valuable tool for monitoring patients as effect of treatment, for the prediction of responders and for diagnostic purposes.


Pentobarbital changes compartmental contribution to cerebral blood flow.
Barbiturates were administered to normal dogs, establishing an isoelectric electrocorticogram. Cortical cerebral blood flows (CBF) and deeper CBF's were respectively measured by krypton-85 (85Kr) and xenon-133 (133 Xe). Following barbiturate administration, the two methods of measuring CBF showed a poor coefficient of variation (r=0.12, p less than 0.05). The cortical flows decreased less than the fast compartment flows. A shifting of percentage contribution of flow to the slow compartment (60% increase, p less than 0.001) was observed after barbiturate infusion. A selective shunting of blood flow to the slower areas may explain the lowering of intracranial pressure and protection of the deep white matter observed by many authors who use barbiturates in clinical an experimental situations.


Late-phase immune responses limiting oocyst survival are independent of TEP1 function yet display strain specific differences in Anopheles gambiae.
There is emerging evidence that mosquito anti-Plasmodium immunity is multimodal with distinct mechanisms for killing malaria parasites at either the ookinete or oocyst stages. Early-phase responses targeting the ookinete require complement-like components circulating in the mosquito hemolymph that result in TEP1-mediated lysis or melanization. Additional responses mediated by the LL3 and STAT pathways limit oocyst survival through unknown mechanisms that require mosquito hemocyte function. While previous experiments argue that these mechanisms of parasite killing are independent, the transient nature of gene-silencing has rendered these experiments inconclusive. To address this issue, we outline experiments using a TALEN-derived TEP1 mutant line to examine the role of TEP1 in the Anopheles gambiae late-phase immune response. Despite higher early oocyst numbers in the TEP1 mutant line, no differences in oocyst survival were observed when compared to control mosquitoes, suggesting that TEP1 function is independent of the late-phase immune response. To further validate this phenotype in the TEP1 mutant, oocyst survival was evaluated in the TEP1 mutant background by silencing either LL3 or STAT-A. Surprisingly, only STAT-A silenced mosquitoes were able to reconstitute the late-phase immune phenotype increasing oocyst survival in the TEP1 mutant line. Additional experiments highlight significant differences in LL3 expression in the M/S hybrid genetic background of the TEP1 mutant line compared to that of the Keele strain (M form) of An. gambiae, and demonstrate that LL3 is not required for granulocyte differentiation in the M/S hybrid G3 genetic background in response to malaria parasite infection. Through the combination of genetic experiments utilizing genetic mutants and reverse genetic approaches, new information has emerged regarding the mechanisms of mosquito late-phase immunity. When combined with previously published experiments, the body of evidence argues that Plasmodium oocyst survival is TEP1 independent, thus establishing that the mechanisms of early- and late-phase immunity are distinct. Moreover, we identify that the known components that mediate oocyst survival are susceptible to strain-specific differences depending on their genetic background and provide further evidence that the signals that promote hemocyte differentiation are required to limit oocyst survival. Together, this study provides new insights into the mechanisms of oocyst killing and the importance of genetics in shaping mosquito vector competence.


Effect of ascorbic acid supplementation on liver and kidney toxicity in cyclophosphamide-treated female albino rats.
Effects of ascorbic acid supplementation on the activity of acid phosphatase (ACP), alkaline phosphatase (ALP), glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) on liver, kidney and serum in cyclophosphamide-treated female virgin rats were investigated. Oral administration of cyclophosphamide at the dose of 5 mg/kg body weight/day for 12 days resulted in a significant elevation in ACP and ALP activities in liver, kidney and serum. Ascorbic acid supplementation at the dose of 25 mg/kg body weight/day showed a significant protection in the activity of ACP in liver, kidney and serum, but only in ALP activity in kidney. ALP activities in liver and serum were not restored to control level by ascorbic acid supplementation. Activities of GOT and GPT were elevated significantly in liver, kidney and serum after cyclophosphamide treatment, and were protected and restored to control level by ascorbic acid supplementation.


Association of aortic and main left coronary aneurysms with severe aortic insufficiency in Takayasu's arteritis.
Takayasu's arteritis is a granulomatous vasculitis of unknown etiology that affects mainly the aorta and its branches. As a result of intimal fibroproliferation, segmental stenosis, occlusion, dilatation, and aneurysmal formation of the involved vessels may develop. It is an uncommon disease and usually affects young Asian female patients during the second and third decades of life. Coronary arteries are exceptionally affected and coronary aneurysm formation is a very rare finding. We describe a case of a previously healthy 26-year-old Caucasian female whose Takayasu's arteritis presented as a previously undescribed association of aortic and main left coronary aneurysms with severe aortic insufficiency.


Human Brain Organoids as an In Vitro Model System of Viral Infectious Diseases.
Brain organoids, or brainoids, have shown great promise in the study of central nervous system (CNS) infection. Modeling Zika virus (ZIKV) infection in brain organoids may help elucidate the relationship between ZIKV infection and microcephaly. Brain organoids have been used to study the pathogenesis of SARS-CoV-2, human immunodeficiency virus (HIV), HSV-1, and other viral infections of the CNS. In this review, we summarize the advances in the development of viral infection models in brain organoids and their potential application for exploring mechanisms of viral infections of the CNS and in new drug development. The existing limitations are further discussed and the prospects for the development and application of brain organs are prospected.


Transboundary movement of shrimp viruses in crustaceans and their products: a special risk?
Shrimp and shrimp products form the most valuable internationally traded fisheries commodity, and the volumes are huge, estimated to be about 3.6 million tonnes. However, despite the existence under the General Agreement on Tariffs and Trade, of the Sanitary and Phytosanitary Measures (SPS Agreement) and the activities of the World Organisation for Animal Health (OIE), viral shrimp epizootics have spread and continue to spread, affecting world production. Though most attention has focussed on the movement of live shrimp product, the spread of new and emerging diseases through other crustaceans and their nonviable products is of increasing concern. The risks associated with the unrestricted movement of nonviable product will be outlined and measures that can be taken to mitigate the risk are discussed. Ultimately, for crustacean diseases, the paradigm under which the OIE has operated for the past 80 years needs to change.


Judging intoxication.
Judgments of whether a person is intoxicated by alcohol are important in a number of civil and law enforcement settings. This paper reviews how well people are able to make such judgments, the evidence for individual signs of intoxication, several structured rating techniques, and the use of sobriety tests. It is concluded that observers relying on common-sense clues of intoxication have limited ability to assess the blood alcohol concentration (BAC) levels of strangers, particularly below .10%. This generalization holds across professions that might be expected to show greater accuracy. Structured assessment instruments based on observable signs have shown promise but are confounded by the wide variations between casual social drinkers and those that have obtained a high level of tolerance. Among sobriety tests, only NHTSA's Standardized Field Sobriety Tests (SFSTs) have substantial, but seriously flawed, research support. Assessing the sobriety of strangers in the low to moderate BAC ranges without resort to chemical tests remains a daunting task.


Using the descending branch of the lateral circumflex femoral artery and vein as recipient vessel for free tissue transfer to the difficult areas of the lower extremity.
Free tissue transfer to the areas around the knee or hip can be difficult because there are limited options for reliable recipient vessels, but extended vein grafts may decrease the chance for success. The purpose of this study was to describe our experience with creating a proper recipient vessel for free flap reconstructions in these areas using the descending branch of the lateral circumflex femoral vessels in the thigh. Two patients underwent free flap reconstruction of a complex knee wound after orthopedic trauma and a complex hip wound after arthroplasty. A contralateral anterior lateral thigh perforator flap and a latissimus dorsi flap were used to close the wounds, respectively. Dissection was carried between the rectus femoris and vastus lateralis and a recipient vessel was created and placed in more desirable location adjacent to the defect for microvascular anastomoses. A long 12-cm recipient vessel measuring 1.5 to 2.5 cm in diameter for both artery and vein was dissected and placed in an area adjacent to the defect for a straightforward microvascular microanastomosis. Both patients had successful free tissue reconstructions with uneventful postoperative recoveries. The flaps remained viable and the wounds healed with follow-up, revealing reliable soft tissue and good contour in the reconstructed areas. The descending branch of the lateral circumflex femoral vessels can be dissected out and serve as a recipient vessel after being placed adjacent to the defect for free tissue transfer to the difficult areas of the lower extremity. Creation of such a recipient vessel would avoid using vein grafts and ease free flap reconstruction to those difficult reconstructive areas.


L-ascorbic acid potentiates endothelial nitric oxide synthesis via a chemical stabilization of tetrahydrobiopterin.
Ascorbic acid has been shown to stimulate endothelial nitric oxide (NO) synthesis in a time- and concentration-dependent fashion without affecting NO synthase (NOS) expression or l-arginine uptake. The present study investigates if the underlying mechanism is related to the NOS cofactor tetrahydrobiopterin. Pretreatment of human umbilical vein endothelial cells with ascorbate (1 microm to 1 mm, 24 h) led to an up to 3-fold increase of intracellular tetrahydrobiopterin levels that was concentration-dependent and saturable at 100 microm. Accordingly, the effect of ascorbic acid on Ca(2+)-dependent formation of citrulline (co-product of NO) and cGMP (product of the NO-activated soluble guanylate cyclase) was abolished when intracellular tetrahydrobiopterin levels were increased by coincubation of endothelial cells with sepiapterin (0.001-100 microm, 24 h). In contrast, ascorbic acid did not modify the pterin affinity of endothelial NOS, which was measured in assays with purified tetrahydrobiopterin-free enzyme. The ascorbate-induced increase of endothelial tetrahydrobiopterin was not due to an enhanced synthesis of the compound. Neither the mRNA expression of the rate-limiting enzyme in tetrahydrobiopterin biosynthesis, GTP cyclohydrolase I, nor the activities of either GTP cyclohydrolase I or 6-pyruvoyl-tetrahydropterin synthase, the second enzyme in the de novo synthesis pathway, were altered by ascorbate. Our data demonstrate that ascorbic acid leads to a chemical stabilization of tetrahydrobiopterin. This was evident as an increase in the half-life of tetrahydrobiopterin in aqueous solution. Furthermore, the increase of tetrahydrobiopterin levels in intact endothelial cells coincubated with cytokines and ascorbate was associated with a decrease of more oxidized biopterin derivatives (7,8-dihydrobiopterin and biopterin) in cells and cell supernatants. The present study suggests that saturated ascorbic acid levels in endothelial cells are necessary to protect tetrahydrobiopterin from oxidation and to provide optimal conditions for cellular NO synthesis.


Tension neck and evaluation of a physical training course among office workers in a bank corporation.
The purpose of this study was to investigate the effects of a physical training course in a group of patients (n = 74) suffering from chronic tension neck. All participants in the course were employed by a bank corporation in Helsinki, Finland. A comparable control group (n = 77) consisted of office workers with tension neck from the same bank corporation who did not attend any training course. The outcome was analysed 6 months after the course. Pain and disability in the neck and shoulder region did not vary significantly between the group which participated in the training course and the control group. The experimental group had increased the amount of physical workout compared to the control group (83.7% vs 69.0%, P = 0.0448). Also, regarding the frequency of relaxation and stretching exercises the two groups differed significantly: the experimental group had continued to perform exercises more often (P = 0.0434). The frequency of sick leave days did not significantly differ between the groups, but the office workers in the experimental group had more periods of extended sick leave (> 10 days) and the controls had more frequent short sick leaves. The experimental group did increase their physical workout significantly compared with the controls, but no differences were detected regarding pain and disability. In order to gain more benefit more attention should be paid to the educational part of the training courses in order to enhance the patients' self-care abilities. Also, strategies to alleviate psychosocial problems and organized relaxation exercises could decrease muscle tension in the neck in office workers.


Defining quality for distal pancreatectomy: does the laparoscopic approach protect patients from poor quality outcomes?
Established systems for grading postoperative complications do not change the assigned grade when multiple interventions or readmissions are required to manage a complication. Studies using these systems may misrepresent outcomes for the surgical procedures being evaluated. We define a quality outcome for distal pancreatectomy (DP) and use this metric to compare laparoscopic distal pancreatectomy (LDP) to open distal pancreatectomy (ODP). Records for patients undergoing DP between January 2006 and December 2009 were reviewed. Clavien-Dindo grade IIIb, IV, and V complications were classified as severe adverse--poor quality--postoperative outcomes (SAPOs). II and IIIa complications requiring either significantly prolonged overall lengths of stay including readmissions within 90 days or more than one invasive intervention were also classified as SAPOs. By Clavien-Dindo system alone, 91 % of DP patients had either no complication or a low/moderate grade (I, II, IIIa) complication. Using our reclassification, however, 25 % had a SAPO. Patients undergoing LDP demonstrated a Clavien-Dindo complication profile identical to that for SDP but demonstrated significantly shorter overall lengths of stay, were less likely to require perioperative transfusion, and less likely to have a SAPO. Established systems undergrade the severity of some complications following DP. Using a procedure-specific metric for quality, we demonstrate that LDP affords a higher quality postoperative outcome than ODP.


Angiotensin converting enzyme inhibition and dihydropyridine calcium channel blockade in the treatment of left ventricular hypertrophy in arterial hypertension.
In arterial hypertension, left ventricular (LV) hypertrophy (H) is a prognostically relevant target organ damage associated with systolic and diastolic LV dysfunction. The level of LV dysfunction seems to be related to the degree of myocardial fibrosis. Prognosis of hypertensive patients who have LVH regression appears to be improved. Therefore, LVH regression is an important antihypertensive treatment goal. The renin-angiotensin-aldosterone system is implicated in LVH development and myocardial fibrosis in essential arterial hypertension. Early studies in the 80s and 90s have led expectations that angiotensin converting enzyme (ACE) inhibitors could induce greater LVH regression than other antihypertensive drugs at similar blood pressure reduction. In the late 90s, the double-blind randomized controlled PRESERVE trial (Prospective Randomize Enalapril Study Evaluating Reversal of Ventricular Enlargement) has been designed to evaluate whether the ACE inhibitor enalapril was more effective than nifedipine GITS in regressing LVH and improving LV diastolic dysfunction. The PRESERVE study demonstrated a mildly higher antihypertensive effect of nifedipine GITS than enalapril, which required more frequently association with hydrochlorothiazide to control blood pressure. However, at similar level of blood pressure reduction achieved with enalapril and long-acting nifedipine in association with hydrochlorothiazide or atenolol, both antihypertensive treatments showed similar efficacy in LVH regression and LV diastolic filling improvement.


The in situ assay of Candida albicans enzymes during yeast growth and germ-tube formation.
Conditions are described for the preparation of permeabilized cells of Candida albicans. This method has been used for the in situ assay of enzymes in both yeast cells and germ-tube forming cells. A mixture of toluene/ethanol/Triton X-100 (1:4:0.2, by vol.) at 15% (v/v) and 8% (v/v) was optimal for the in situ assay of glucose-6-phosphate dehydrogenase in yeast and germ-tube forming cells, respectively. The concentration of toluene/ethanol/Triton X-100 required for optimal in situ activity of other enzymes was influenced by the cellular location of the enzyme, growth phase and morphology. The membrane-bound enzymes (chitin synthase, glucan synthase, ATPase), cytosolic enzymes (glucose-6-phosphate dehydrogenase, isocitrate dehydrogenase, pyruvate kinase, phosphofructokinase, alkaline phosphatase, glucosamine-6-phosphate deaminase and N-acetylglucosamine kinase) and wall enzymes (beta-glucosidase and acid phosphatase) were measured and compared to the activity obtained in cell extracts. The pattern of enzyme induction and the properties of the allosteric enzymes phosphofructokinase and pyruvate kinase were measured in situ. Pyruvate kinase in situ was homotropic for phosphoenolpyruvate with a Hill coefficient of 1.9 and a S0.5 of 0.6 mM, whereas in cell extracts, it had a Hill coefficient of 1.9 and a S0.5 of 1.0 mM. The Km for ATP was 1.6 mM in cell extracts and 1.8 mM in permeabilized cells. In situ phosphofructokinase was homotropic for fructose 6-phosphate (S0.5 of 2.3 mM, Hill coefficient of 4.0). The kinetic properties of pyruvate kinase and phosphofructokinase measured in situ or in vitro were similar for both yeast cells and germ-tube forming cells.


FPs have vital role in ensuring success of breast cancer screening programs.
SCREENING IS THE ONLY PROVEN STRATEGY for reducing breast cancer mortality in women older than 50. Over the last 9 years, 8 provinces and 2 (territories have established independent dedicated mammography programs. A recent workshop on screening programs was told that family physicians play a crucial role in the ultimate success of these programs because of their referral role.


Treatment Response to Botulinum Neurotoxin-A in Children With Cerebral Palsy Categorized by the Type of Stretch Reflex Muscle Activation.
While Botulinum NeuroToxin-A (BoNT-A) injections are frequently used to reduce the effects of hyperactive stretch reflexes in children with cerebral palsy (CP), the effects of this treatment vary strongly. Previous research, combining electromyography (EMG) with motion analysis, defined different patterns of stretch reflex muscle activation in muscles, those that reacted more to a change in velocity (velocity dependent -VD), and those that reacted more to a change in length (length dependent -LD). The aim of this study was to investigate the relation between the types of stretch reflex muscle activation in the semitendinosus with post-BoNT-A outcome as assessed passively and with 3D gait analysis in children with spastic CP. Eighteen children with spastic CP (10 bilaterally involved) between the ages of 12 and 18 years were assessed before and on average, 8 weeks post-treatment. EMG and motion analysis were used to assess the degree and type of muscle activation dependency in the semitendinosus during passive knee extensions performed at different joint angular velocities. Three-dimensional gait analysis was used to assess knee gait kinematics as a measure of functional outcome. Pre-treatment, 9 muscles were classified as VD and 9 as LD, but no differences between the groups were evident in the baseline knee gait kinematics. Post-treatment, stretch reflex muscle activation decreased significantly in both groups but the reduction was more pronounced in those muscles classified pre-treatment as VD (-72% vs. -50%, p = 0.005). In the VD group, these changes were accompanied by greater knee extension at initial contact and during the swing phase of gait. In the LD group, there was significantly increased post-treatment knee hyperextension in late stance. Although results vary between patients, the reduction of stretch reflex muscle activation in the semitendinosus generally translated to an improved functional outcome, as assessed with 3D gait analysis. However, results were less positive for those muscles with pre-treatment length-dependent type of stretch reflex muscle activation. The study demonstrates the relevance of categorizing the type of stretch reflex muscle activation as a possible predictor of treatment response.


A gene involved in modifying transfer RNA is required for fungal pathogenicity and stress tolerance of Colletotrichum lagenarium.
7-Methylguanosine (m7G) modification of tRNA occurs widely in prokaryotes and eukaryotes, although information about its biological roles is limited. Here, we report that a gene involved in m7G modification of tRNA is required for infection by the phytopathogenic fungus Colletotrichum lagenarium. Analysis of the infection-deficient mutant of C. lagenarium, produced by plasmid insertional mutagenesis, identified a tagged gene that is designated APH1. The aph1 mutants, generated by targeted gene disruption, exhibit significant reduction in pathogenicity on the host plants. We conclude that APH1 is required for fungal infection in C. lagenarium. Aph1 showed a strong similarity to Saccharomyces cerevisiae Trm8 involved in m7G modification of tRNA. The m7G content of tRNA from the aph1 deletion mutant was severely reduced compared with that from the wild type, indicating that APH1 is required for m7G methyltransferase activity. Appressoria formed by the aph1 mutants developed penetration hyphae into cellophane, suggesting that appressoria of the mutants retain basic function for penetration. However, the aph1 mutants failed to develop intracellular penetration hyphae into epidermis of the host plants, suggesting a specific requirement of APH1 for appressorium-mediated host invasion. The mutants also had increased sensitivity to salinity and H2O2 stresses. Interestingly, a heat shock treatment on the host plants enabled the aph1 mutant to penetrate them. These data suggest that the APH1 is required for the plant invasion, probably to overcome environmental stresses derived from basal preinvasion (penetration) defence of the host plants.


Knowledge, attitude and practice related to chemical hazards and personal protective equipment among particleboard workers in Ethiopia: a cross-sectional study.
Work in the wood industry is often associated with exposure to wood dust and formaldehyde. The aims of this study were to describe the Knowledge, Attitude and Practice (KAP) concerning chemical health hazards among particleboard workers and to compare the KAP among temporary and permanent workers. A cross-sectional study design was used to collect data by structured questionnaires in two particleboard factories in Ethiopia. A total of 159 workers and 13 management personnel participated in this study. Both closed-ended and open-ended questions were included in the interviews. Chi-square tests, T tests and correlation analyses were used for categorical and continuous data. Total knowledge score (range 0-8) was calculated as the sum score of 8 items weighing one point each. Multiple linear regression was applied to estimate the impact of employment status on total knowledge score adjusted for level of education. Content analysis was applied to analyse collected data from open-ended questions. The mean age of the respondents was 28 (SD = 6) years and on average they had 3.7 [3] years of service. The permanent workers were older than the temporary workers (29 vs 26 years, p = 0.001), and a considerably high fraction of the permanent workers had vocational education (90%) compared to the temporary workers (11%). Permanent workers had higher proportion of response on knowledge of 10 of 12 topics regarding chemical hazards and attitudes on 6 of 11 of these topics than temporary workers. Permanent workers had higher knowledge scores (3.7) compared to temporary workers (1.3) (p < 0.001), also after adjusting for education (p = 0.011). Permanent workers were provided with personal protective equipment (PPE) while temporary workers were not. The qualitative data helps to understand the workers and administrative personnel attitude and thinking regarding chemical hazards and PPE. The findings revealed that permanent workers have higher proportion of positive response on knowledge and attitude towards chemical health hazards than temporary workers. However, practice in use of PPE depended on access to PPE. Few temporary workers were provided with PPE.


Virulence determines beneficial trade-offs in the response of virus-infected plants to drought via induction of salicylic acid.
It has been hypothesized that plants can get beneficial trade-offs from viral infections when grown under drought conditions. However, experimental support for a positive correlation between virus-induced drought tolerance and increased host fitness is scarce. We investigated whether increased virulence exhibited by the synergistic interaction involving Potato virus X (PVX) and Plum pox virus (PPV) improves tolerance to drought and host fitness in Nicotiana benthamiana and Arabidopsis thaliana. Infection by the pair PPV/PVX and by PPV expressing the virulence protein P25 of PVX conferred an enhanced drought-tolerant phenotype compared with single infections with either PPV or PVX. Decreased transpiration rates in virus-infected plants were correlated with drought tolerance in N. benthamiana but not in Arabidopsis. Metabolite and hormonal profiles of Arabidopsis plants infected with the different viruses showed a range of changes that positively correlated with a greater impact on drought tolerance. Virus infection enhanced drought tolerance in both species by increasing salicylic acid accumulation in an abscisic acid-independent manner. Viable offspring derived from Arabidopsis plants infected with PPV increased relative to non-infected plants, when exposed to drought. By contrast, the detrimental effect caused by the more virulent viruses overcame potential benefits associated with increased drought tolerance on host fitness.


Mini-implants and miniplates generate sub-absolute and absolute anchorage.
The functional demand imposed on bone promotes changes in the spatial properties of osteocytes as well as in their extensions uniformly distributed throughout the mineralized surface. Once spatial deformation is established, osteocytes create the need for structural adaptations that result in bone formation and resorption that happen to meet the functional demands. The endosteum and the periosteum are the effectors responsible for stimulating adaptive osteocytes in the inner and outer surfaces. Changes in shape, volume and position of the jaws as a result of skeletal correction of the maxilla and mandible require anchorage to allow bone remodeling to redefine morphology, esthetics and function as a result of spatial deformation conducted by orthodontic appliances. Examining the degree of changes in shape, volume and structural relationship of areas where mini-implants and miniplates are placed allows us to classify mini-implants as devices of subabsolute anchorage and miniplates as devices of absolute anchorage.


Extended-representation bisulfite sequencing of gene regulatory elements in multiplexed samples and single cells.
The biological roles of DNA methylation have been elucidated by profiling methods based on whole-genome or reduced-representation bisulfite sequencing, but these approaches do not efficiently survey the vast numbers of non-coding regulatory elements in mammalian genomes. Here we present an extended-representation bisulfite sequencing (XRBS) method for targeted profiling of DNA methylation. Our design strikes a balance between expanding coverage of regulatory elements and reproducibly enriching informative CpG dinucleotides in promoters, enhancers and CTCF binding sites. Barcoded DNA fragments are pooled before bisulfite conversion, allowing multiplex processing and technical consistency in low-input samples. Application of XRBS to single leukemia cells enabled us to evaluate genetic copy number variations and methylation variability across individual cells. Our analysis highlights heterochromatic H3K9me3 regions as having the highest cell-to-cell variability in their methylation, likely reflecting inherent epigenetic instability of these late-replicating regions, compounded by differences in cell cycle stages among sampled cells.


Aerosol optical properties and direct radiative forcing at Taihu.
Ground-based characteristics (optical, type, size, and radiative properties) of aerosols measured between 2005 and 2012 were investigated over the Taihu rim region, which encompasses the cities of Shanghai, Suzhou, Wuxi, and Changzhou. The aerosol optical depth (AOD) showed a distinct seasonal variation with the highest value in summer and the lowest AOD in winter. There was broadest frequency distribution with a multimodal structure in summer. The Ångström exponent (AE) showed high values during spring; the relative frequency of AE in the range of 0-0.8 was 5-10 times greater than that of other seasons. The samples with high AOD440 and low AE440-870 were mainly observed in spring, which is attributed to the relative abundance of coarse particles. The monthly aerosol volume size distributions presented a bimodal structure (fine and coarse modes). The coarse mode was dominant during spring, while the fine mode was predominant in other seasons. The main aerosol type over Taihu during all the seasons was the mixed small-particle category, followed by the urban/industrial category. The minimum single scattering albedo (SSA) occurred in winter, suggesting that atmosphere aerosol had a higher absorption. All monthly averaged asymmetry factors (ASY) had positive values and no distinct seasonal variation. Both high real (Re) and imaginary (Im) parts of the refractive index occurred in winter. The atmospheric warming effect of aerosol was more significant in winter compared with other seasons, with the averaged atmosphere aerosol radiative forcing (ARF) and the corresponding atmospheric heating rate up to +69.46 W·m-2 and 1.95 K·day-1, respectively. There existed a significant positive correlation between AOD and ARF (absolute value), and the correlation coefficients (r) exceeded 0.86 in each season with maximum r in summer. Along with the increasing of the SSA, the aerosol radiative forcing efficiency (absolute value) showed a decreasing trend at the bottom of the atmosphere and an increasing trend at the top of the atmosphere.


Evaluation of the Radiomics Method for the Prediction of Atypical Adenomatous Hyperplasia in Patients With Subcentimeter Pulmonary Ground-Glass Nodules.
We aimed to develop a prediction model to distinguish atypical adenomatous hyperplasia (AAH) from early lung adenocarcinomas in patients with subcentimeter pulmonary ground-glass nodules (GGNs), which may help avoid aggressive surgical resection for patients with AAH. Surgically confirmed cases of AAH and lung adenocarcinomas manifesting as GGNs of less than 1 cm were retrospectively collected. A prediction model based on radiomics and clinical features identified from a training set of cases was built to differentiate AAH from lung adenocarcinomas and tested on a validation set. Four hundred and eighty-five eligible cases were included and randomly assigned to the training (n = 339) or the validation sets (n = 146). The developed radiomics prediction model showed good discrimination performance to distinguish AAH from adenocarcinomas in both the training and the validation sets, with, respectively, 84.1% and 82.2% of accuracy, and AUCs of 0.899 (95% CI: 0.867-0.931) and 0.881 (95% CI: 0.827-0.936). The prediction model based on radiomics and clinical features can help differentiate AAH from adenocarcinomas manifesting as subcentimeter GGNs and may prevent aggressive resection for AAH patients, while reserving this treatment for adenocarcinomas.


The default mode network and the working memory network are not anti-correlated during all phases of a working memory task.
The default mode network and the working memory network are known to be anti-correlated during sustained cognitive processing, in a load-dependent manner. We hypothesized that functional connectivity among nodes of the two networks could be dynamically modulated by task phases across time. To address the dynamic links between default mode network and the working memory network, we used a delayed visuo-spatial working memory paradigm, which allowed us to separate three different phases of working memory (encoding, maintenance, and retrieval), and analyzed the functional connectivity during each phase within and between the default mode network and the working memory network networks. We found that the two networks are anti-correlated only during the maintenance phase of working memory, i.e. when attention is focused on a memorized stimulus in the absence of external input. Conversely, during the encoding and retrieval phases, when the external stimulation is present, the default mode network is positively coupled with the working memory network, suggesting the existence of a dynamically switching of functional connectivity between "task-positive" and "task-negative" brain networks. Our results demonstrate that the well-established dichotomy of the human brain (anti-correlated networks during rest and balanced activation-deactivation during cognition) has a more nuanced organization than previously thought and engages in different patterns of correlation and anti-correlation during specific sub-phases of a cognitive task. This nuanced organization reinforces the hypothesis of a direct involvement of the default mode network in cognitive functions, as represented by a dynamic rather than static interaction with specific task-positive networks, such as the working memory network.


Iodonium Initiators: Paving the Air-free Oxidation of Spiro-OMeTAD for Efficient and Stable Perovskite Solar Cells.
To date, perovskite solar cells (pero-SCs) with doped 2,2',7,7'-tetrakis(N,N-di-p-methoxyphenylamine)-9,9'-spirobifluorene (Spiro-OMeTAD) hole transporting layers (HTLs) have shown the highest recorded power conversion efficiencies (PCEs). However, their commercialization is still impeded by poor device stability owing to the hygroscopic lithium bis(trifluoromethanesulfonyl)imide and volatile 4-tert-butylpyridine dopants as well as time-consuming oxidation in air. In this study, we explored a series of single-component iodonium initiators with strong oxidability and different electron delocalization properties to precisely manipulate the oxidation states of Spiro-OMeTAD without air assistance, and the oxidation mechanism was clearly understood. Iodine (III) in the diphenyliodonium cation (IP+) can accept a single electron from Spiro-OMeTAD and forms Spiro-OMeTAD•+ owing to its strong oxidability. Moreover, because of the coordination of the strongly delocalized TFSI- with Spiro-OMeTAD•+ in a stable radical complex, the resulting hole mobility was 30 times higher than that of pristine Spiro-OMeTAD. In addition, the IP-TFSI initiator facilitated the growth of a homogeneous and pinhole-free Spiro-OMeTAD film. The pero-SCs based on this oxidizing HTL showed excellent efficiencies of 25.16% (certified: 24.85% for 0.062-cm2) and 20.71% for a 15.03-cm2 module as well as remarkable overall stability.


Overexpression of CD39 in mouse airways promotes bacteria-induced inflammation.
In airways, the ecto-nucleoside triphosphate diphosphohydrolase CD39 plays a central role in the regulation of physiological mucosal nucleotide concentrations and likely contributes to the control of inflammation because accelerated ATP metabolism occurs in chronic inflammatory lung diseases. We sought to determine whether constant elevated CD39 activity in lung epithelia is sufficient to cause inflammation and whether this affects the response to acute LPS or Pseudomonas aeruginosa exposure. We generated transgenic mice overexpressing human CD39 under the control of the airway-specific Clara cell 10-kDa protein gene promoter. Transgenic mice did not develop any spontaneous lung inflammation. However, intratracheal instillation of LPS resulted in accelerated recruitment of neutrophils to the airways of transgenic mice. Macrophage clearance was delayed, and the amounts of CD8(+) T and B cells were augmented. Increased levels of keratinocyte chemoattractant, IL-6, and RANTES were produced in transgenic lungs. Similarly, higher numbers of neutrophils and macrophages were found in the lungs of transgenic mice infected with P. aeruginosa, which correlated with improved bacteria clearance. The transgenic phenotype was partially and differentially restored by coinstillation of P2X(1) or P2X(7) receptor antagonists or of caffeine with LPS. Thus, a chronic increase of epithelial CD39 expression and activity promotes airway inflammation in response to bacterial challenge by enhancing P1 and P2 receptor activation.


Toxicity and outcome of children and adolescents participating in phase I/II trials of novel anticancer drugs: the Royal Marsden experience.
Early phase trials are crucial in developing new therapies for poor prognosis childhood malignancies. Outcomes and toxicities of children treated on phase I/II trials at the Royal Marsden, one of the largest pediatric oncology early phase trial units in Europe, were examined to provide a baseline dataset and generate hypotheses. All patients recruited over a 10-year period to December 2011 were included. Variables including baseline characteristics, time on study, survival, toxicities, and admissions were collected. Seventy-two patients were recruited to 21 trials (5 phase I, 16 phase II; overall 12 involved molecularly targeted agents). Median age at consent was 12.4 years. Dose-limiting toxicities were rare in phase I trial participants (2 of 15 evaluable patients, 13%); the most common reason for leaving trials was disease progression (76%), rather than drug toxicity (1.7%). Median time on trial was 1.3 months (phase I patients) and 3.3 months (phase II). Early phase trials in children are safe and unexpected toxic side effects are infrequent. Patients and their families are willing to travel to access novel therapies, although the overall prognosis for these individuals is poor. Continued expansion of the portfolio is needed ultimately to improve the outcomes for those with resistant disease.


Preclinical Models of Ovarian Cancer: Pathogenesis, Problems, and Implications for Prevention.
Preclinical models are relatively underutilized and underfunded resources for modeling the pathogenesis and prevention of ovarian cancers. Several reviews have detailed the numerous published models of ovarian cancer. In this review, we will provide an overview of experimental model systems, their strengths and limitations, and use selected models to illustrate how they can be used to address specific issues about ovarian cancer pathogenesis. We will then highlight some of the preclinical prevention studies performed to date and discuss experiments needed to address important unanswered questions about ovarian cancer prevention strategies.


TIMING OF SEXUAL DEBUT AMONG UNMARRIED YOUTHS AGED 15-24 YEARS IN SUB-SAHARAN AFRICA.
This study aimed to contribute to the evidence on the timing of sexual debut in young people in sub-Saharan African countries. Data were extracted from 34 nationally representative surveys conducted in the region between 2006 and 2014. The study sample comprised unmarried women (n=167,932) and men (n=76,900) aged 15-24 years. Descriptive techniques and Cox proportional regression models were used to estimate the timing of sexual debut, and Kaplan-Meier hazard curves were used to describe the patterns of sexual debut in each country by sex. For the countries studied, sexual debut for both women and men occurred between the ages of 15 and 18 years, with median ages of 16 for women and 17 for men. Overall, education and household wealth provided significant protection against early sexual debut among women, but the reverse was found among men for wealth. Women in rural areas, in female-headed households and in Central, South and West Africa reported higher hazards of early commencement of sexual activity than their counterparts in urban, male-headed households and East Africa. However, the impact of these variables on male sexual debut did not follow a consistent pattern. Varied timing, as well as country-specific risk factors associated with sexual debut for young women and men across sub-Saharan Africa, were identified. Sexual health programmes and interventions for young people may require different approaches for young women and men.


Laminar flow air cleaner bed attachment: a controlled trial.
Thirteen house dust mite-allergic young asthmatics were entered into a double-blind, crossover clinical trial to compare "in use" with "non-use" of a laminar flow air cleaner bed attachment. The study design encouraged maintenance of symptom control by adjustment of the dose of medications used. There was a significant reduction in the amount of medications required by the patients during the trial period that the air cleaner was in use. Histamine airway responsiveness was significantly decreased for a group of eight of the subjects tested at the end of a 3-month open trial.


Object segmentation and labeling by learning from examples.
We propose a system that employs low-level image segmentation followed by color and two-dimensional (2-D) shape matching to automatically group those low-level segments into objects based on their similarity to a set of example object templates presented by the user. A hierarchical content tree data structure is used for each database image to store matching combinations of low-level regions as objects. The system automatically initializes the content tree with only "elementary nodes" representing homogeneous low-level regions. The "learning" phase refers to labeling of combinations of low-level regions that have resulted in successful color and/or 2-D shape matches with the example template(s). These combinations are labeled as "object nodes" in the hierarchical content tree. Once learning is performed, the speed of second-time retrieval of learned objects in the database increases significantly. The learning step can be performed off-line provided that example objects are given in the form of user interest profiles. Experimental results are presented to demonstrate the effectiveness of the proposed system with hierarchical content tree representation and learning by color and 2-D shape matching on collections of car and face images.


Structural insights into the functional versatility of WW domain-containing oxidoreductase tumor suppressor.
Recent work on WW domain-containing oxidoreductase (WWOX) tumor suppressor is beginning to shed new light on both the molecular mechanism of action of its WW domains as well as the contiguous catalytic domain. Herein, the structural basis underlying the ability of WW1 domain to bind to various physiological ligands and how the orphan WW2 tandem partner synergizes its ligand binding in the context of WW1-WW2 tandem module of WWOX is discussed. Notably, the WW domains within the WW1-WW2 tandem module physically associate so as to adopt a fixed spatial orientation relative to each other. In this manner, the association of WW2 domain with WW1 hinders ligand binding to the latter. Consequently, ligand binding to WW1 domain not only results in the displacement of WW2 lid but also disrupts the fixed orientation of WW domains in the liganded conformation. Equally importantly, structure-guided functional approach suggests that the catalytic domain of WWOX likely serves as a retinal oxidoreductase that catalyzes the reversible oxidation and reduction of all-trans-retinal. Collectively, this review provides structural insights into the functional versatility of a key signaling protein with important implications on its biology.


A loss-of-function variant in OSBPL1A predisposes to low plasma HDL cholesterol levels and impaired cholesterol efflux capacity.
Among subjects with high-density-lipoprotein cholesterol (HDL-C) below the 1st percentile in the general population, we identified a heterozygous variant OSBPL1A p.C39X encoding a short truncated protein fragment that co-segregated with low plasma HDL-C. We investigated the composition and function of HDL from the carriers and non-carriers and studied the properties of the mutant protein in cultured hepatocytes. Plasma HDL-C and apolipoprotein (apo) A-I were lower in carriers versus non-carriers, whereas the other analyzed plasma components or HDL parameters did not differ. Sera of the carriers displayed a reduced capacity to act as cholesterol efflux acceptors (p < 0.01), whereas the cholesterol acceptor capacity of their isolated HDL was normal. Fibroblasts from a p.C39X carrier showed reduced cholesterol efflux to lipid-free apoA-I but not to mature HDL particles, suggesting a specific defect in ABCA1-mediated efflux pathway. In hepatic cells, GFP-OSBPL1A partially co-localized in endosomes containing fluorescent apoA-I, suggesting that OSBPL1A may regulate the intracellular handling of apoA-I. The GFP-OSBPL1A-39X mutant protein remained in the cytosol and failed to interact with Rab7, which normally recruits OSBPL1A to late endosomes/lysosomes, suggesting that this mutation represents a loss-of-function. The present work represents the first characterization of a human OSBPL1A mutation. Our observations provide evidence that a familial loss-of-function mutation in OSBPL1A affects the first step of the reverse cholesterol transport process and associates with a low HDL-C phenotype. This suggests that rare mutations in OSBPL genes may contribute to dyslipidemias.


Tag1 is an autonomous transposable element that shows somatic excision in both Arabidopsis and tobacco.
Tag1 is a transposable element first identified as an insertion in the CHL1 gene of Arabidopsis. The chl1::Tag1 mutant originated from a plant (ecotype Landsberg erecta) that had been transformed with the maize transposon Activator (Ac), which is distantly related to Tag1. Genomic analysis of untransformed Landsberg erecta plants demonstrated that two identical Tag1 elements are present in the Landsberg erecta genome. To determine what provides transposase function for Tag1 transposition, we examined Tag1 excision in different genetic backgrounds. First, the chl1::Tag1 mutant was backcrossed to untransformed wild-type Arabidopsis plants to remove the Ac element(s) from the genome. F2 progeny that had no Ac elements but still retained Tag1 in the CHL1 gene were identified. Tag1 still excised in these Ac-minus progeny producing CHL1 revertants; therefore, Ac is not required for Tag1 excision. Next, Tag1 was inserted between a cauliflower mosaic virus 35S promoter and a beta-glucuronidase (GUS) marker gene and transformed into tobacco. Transformants showed blue-staining sectors indicative of Tag1 excision. Transgenic tobacco containing a defective Tag1 element, which was constructed in vitro by deleting an internal 1.4-kb EcoRI fragment, did not show blue-staining sectors. We conclude that Tag1 is an autonomous element capable of independent excision. The 35S-GUS::Tag1 construct was then introduced into Arabidopsis. Blue-staining sectors were found in cotyledons, leaves, and roots, showing that Tag1 undergoes somatic excision during vegetative development in its native host.


Microwave-plasma dry-etch for fabrication of conducting polymer microelectrodes.
An inexpensive dry etch technology based on a low-pressure microwave plasma generated in a countertop microwave oven is characterized for the patterning of a conductive polymer microelectrode. The etch process is described, and the microwave-generated plasma is characterized by emission spectroscopy. The plasma is generated with an atmospheric mixture of mostly nitrogen and oxygen. A 10 μm wide band microelectrode composed of PEDOT:Tosylate, an optically transparent conductive polymer, is fabricated on a plastic substrate. Conductive polymer etch rates are approximately 280-300 nm/minute. A patterned microelectrode is characterized by atomic force microscopy. The horizontal distance of a 10-90% height of a plasma-etched 150 nm thick electrode was measured to be 360 ± 200 nm (n = 5). Electrodes are further characterized using steady-state cyclic voltammetry, and they have an electroactive area congruent with their geometric area. Finally, a complete device is assembled and used as a separation platform for biogenic amines. A microwave-etched 250 μm PEDOT:PSS electrode is employed for end-channel electrochemical detection on this microchip, where an electrophoretic separation of dopamine and catechol and a micellar electrokinetic chromatography separation of dopamine and serotonin are performed. Both mass and concentration LODs are comparable to other electrochemical detectors in an end-channel configuration. With the added advantages of easy processing, robustness, optical transparency, and low cost, we expect microwave-etched polymer films to be a viable alternative to traditional electrodes.


Neutrophil-to-lymphocyte ratio is a prognostic factor for colon cancer: a propensity score analysis.
A large number of patients suffer recurrence after curative resection, and mortality from colon cancer remains high. The role of systemic inflammatory response, as reflected by neutrophil-to-lymphocyte ratio (NLR), in cancer recurrence and death has been increasingly recognized. This study aimed to analyze long-term oncologic outcomes of Stage II-III colon cancer to examine the prognostic value of NLR using a propensity score analysis. A total of 375 patients with colon cancer underwent radical surgery between 2000 and 2014 at Tokyo Medical University Hospital. Long-term oncologic outcomes of these patients were evaluated according to NLR values. A cut-off NLR of 3.0 was used based on receiver operating characteristic curve analysis. Primary outcomes were overall survival (OS) and relapse-free survival (RFS). An analysis of outcomes according to tumor sidedness was also performed. Patients with lower NLR values ("lower NLR group") were more likely to have lymph node metastasis compared to those with higher NLR values ("higher NLR group") before case matching. After case matching, clinical outcomes were similar between the two groups. There were no significant differences in 5-year OS and 5-year RFS rates between the two groups before case matching based on propensity scores. After case matching, 5-year OS rates were 94.5% in the lower NLR group (n = 135) and 87.0% in the higher NLR group (n = 135), showing a significant difference (p = 0.042). Five-year RFS rates were 87.8% in the lower NLR group and 77.9% in the higher NLR group, also showing a significant difference (p = 0.032). Among patients with left-sided colon cancer in the matched cohort, 5-year OS and 5-year RFS rates were 95.2 and 87.3% in the lower NLR group (n = 88), respectively, and 86.4 and 79.2% in the higher NLR group (n = 71), respectively, showing significant differences (p = 0.014 and p = 0.047, respectively). The NLR is an important prognostic factor for advanced colon cancer, especially for left-sided colon cancer.


Cyclophilin-D binds strongly to complexes of the voltage-dependent anion channel and the adenine nucleotide translocase to form the permeability transition pore.
A cyclophilin-D affinity matrix was employed to isolate components of the mitochondrial permeability transition pore. A cDNA encoding cyclophilin-D was cloned from a rat liver library and ligated into pGEX to allow expression of a glutathione S-transferase/cyclophilin-D fusion protein in Escherichia coli XL1 cells. The cyclophilin-D in the fusion was functionally normal as judged by its peptidylprolyl cis-trans-isomerase activity and its inhibition by cyclosporin A. The fusion protein was bound to glutathione-agarose to form the cyclophilin-D affinity matrix. The matrix selectively bound 32-kDa proteins of mitochondrial membrane extracts, but no H2O-soluble proteins were bound. The 32-kDa band on SDS/PAGE resolved into a doublet and reacted with antibodies against the voltage-dependent anion channel (porin) and the adenine nucleotide translocase. These two proteins were also selectively retained by the affinity matrix in the presence of cyclosporin A. The thus-purified voltage-dependent anion channel, adenine nucleotide translocase and the fusion protein were incorporated into phosphatidylcholine liposomes containing fluorescein sulphonate. The proteoliposomes were permeabilized by Ca2+ plus phosphate, and this was blocked completely by cyclosporin A. These properties are identical to those of the permeability transition pore in mitochondria. It is concluded that the basic permeability transition pore structure comprises the voltage-dependent anion channel (outer membrane), adenine nucleotide translocase (inner membrane) and cyclophilin-D, and forms at contact sites between the two membranes.


Inhibitor-sensitive AmpC beta-lactamase variant produced by an Escherichia coli clinical isolate resistant to oxyiminocephalosporins and cephamycins.
Escherichia coli HKY28, a ceftazidime-resistant strain isolated from a urine specimen in Japan, produced an inhibitor-sensitive AmpC beta-lactamase variant. The deduced amino acid sequence of the enzyme contained a number of substitutions and a tripeptide deletion (Gly286-Ser287-Asp288) compared with the sequence of native AmpC of E. coli. When the deletion was reverted by a 9-base insertion at the relevant site of ampC in the clone, the typical inhibitor-resistant phenotype of AmpC was restored, while at the same time the levels of resistance to ceftazidime, cefpirome, and cefepime were reduced eightfold or more. Molecular modeling studies indicated that a structural change took place in the H-10 helix as a result of the deletion, and this change caused an alteration of the substrate binding site, leading to a unique phenotype analogous to that of inhibitor-sensitive class A extended-spectrum beta-lactamases. The degree of inhibition was greater with sulbactam and tazobactam than with clavulanic acid. To our knowledge, this is the first report to have characterized an E. coli ampC that encodes chromosomal AmpC beta-lactamase sensitive to the available beta-lactamase inhibitors.


Over-expression of an FT-homologous gene of apple induces early flowering in annual and perennial plants.
The protein encoded by the FLOWERING LOCUS T (FT) gene from Arabidopsis thaliana seems to be the long-searched florigen, and over-expression of FT orthologues resulted in accelerated flower development in annual and perennial plants. In the present study, we isolated two allelic mRNA sequences of an FT-homologous gene from apple, which was designated as MdFT1. Using a SSR motif this gene was mapped on LG 12 of apple. Over-expression of MdFT1 in Arabidopsis and the commercially important tree species poplar and apple itself using the CaMV 35S or the Arabidopsis Suc2 promoter resulted in significant accelerated flowering compared with wild-type plants. Transgenic T(0) plants of Arabidopsis flowered 4-6 days on average earlier than wild-type Arabidopsis under LD conditions. Under short-day conditions Suc2::MdFT1 plants of the T(1)-generation flowered after 66 ± 18 days, while wild-type plants flowered about 22 days later. All transgenic Arabidopsis plants showed a normal habit except for the early flowering phenotype. Early flowering was detected 6-10 months after transformation in transgenic polar clones containing MdFT1 driven by the CaMV 35S, whereas plants of the transgenic apple clone T780 set up its first flowers during in vitro cultivation. Based on our results we conclude that MdFT1 is responsible for inducing flowering and that the function of the apple FT1 gene is conserved in annual herbaceous species as well as perennial woody species. Furthermore, we discuss the role of MdFT1 in flower development with regard to the findings of genetic studies on apple.


Ethical issues of cost effectiveness analysis and guideline setting in mental health care.
This article discusses ethical issues which are raised as a result of the introduction of economic evidence in mental health care in order to rationalise clinical practice. Cost effectiveness studies and guidelines based on such studies are often seen as impartial, neutral instruments which try to reduce the influence of non-scientific factors. However, such rationalising instruments often hide normative assumptions about the goals of treatment, the selection of treatments, the role of the patient, and the just distribution of scarce resources. These issues are dealt with in the context of increased control over clinical practice by third parties. In particular, health insurers have a great interest in economic evidence in clinical care settings in order to control access to and quality of (mental) health care. The authors conclude that guideline setting and cost effectiveness analysis may be seen as important instruments for making choices in health care, including mental health care, but that such an approach should always go hand in hand with a social and political debate about the goals of medicine and (mental) health care. This article is partly based on the results of a research project on the normative aspects of guideline setting in psychiatry and cardiology which was conducted under the guidance of the Royal Dutch Medical Association.


Redesigning the response to patients with trauma.
In 2008, a multidisciplinary team of nurses, doctors, clerical staff, a social worker and paramedic at Westmead Hospital, Sydney, New South Wales, began a project to redesign the composition and practice of the hospital's trauma team. This article describes the process involved and explains why staff collaboration, the involvement of stakeholders and the sponsorship of the hospital executive team were crucial to the success of the project. These principles can be transferred to other hospitals.


Myocardial contrast echocardiography can be used to quantify intramyocardial blood volume: new insights into structural mechanisms of coronary autoregulation.
Changes in intramyocardial blood volume (IBV) mediate autoregulatory adaptations to coronary stenosis. This study investigated whether (1) myocardial contrast echocardiography (MCE) can quantify changes in IBV during coronary stenosis and (2) the relation between coronary resistance- and MCE-derived IBV could yield insight into structural mechanisms of IBV change. A circulating in vitro model with constant flow and varying volume was used to determine whether indicator dilution theory could be applied to MCE. Contrast echo was performed with albumin microbubbles, and time-intensity data were fit to a gamma-variate function. With six different volumes, bubble transit time was linearly related to volume (r=.91). To determine whether changes in IBV could be quantified in vivo, the left anterior descending coronary artery in 12 dogs was instrumented with a flow probe, occluder, and intracoronary pressure catheter, and non-flow-limiting stenoses were created. IBV was derived by use of coronary resistance measurements applied to models that assumed autoregulation to occur via vasodilatation or microvascular recruitment. MCE-IBV was calculated from microbubble transit rates. At constant flow, MCE and resistance IBV increased with stenosis. Although MCE and resistance IBV were linearly related, MCE overestimated IBV derived from the vasodilatation model and underestimated IBV calculated from the recruitment model. MCE can quantify autoregulatory increases in IBV that maintain resting myocardial perfusion. These data suggest that both microvessel vasodilatation and recruitment are dual mechanisms of IBV change. MCE thus may be a clinically useful technique for the detection and quantification of coronary artery disease at rest.


Ginger compress therapy for adults with osteoarthritis.
This paper is a report of a study to explicate the phenomenon of ginger compresses for people with osteoarthritis. Osteoarthritis is claimed to be the leading cause of musculoskeletal pain and disability in Western society. Management ideally combines non-pharmacological strategies, including complementary therapies and pain-relieving medication. Ginger has been applied externally for over a thousand years in China to manage arthritis symptoms. Husserlian phenomenological methodology was used and the data were collected in 2007. Ten purposively selected adults who had suffered osteoarthritis for at least a year kept daily diaries and made drawings, and follow-up interviews and telephone conversations were conducted. Seven themes were identified in the data: (1) Meditative-like stillness and relaxation of thoughts; (2) Constant penetrating warmth throughout the body; (3) Positive change in outlook; (4) Increased energy and interest in the world; (5) Deeply relaxed state that progressed to a gradual shift in pain and increased interest in others; (6) Increased suppleness within the body and (7) More comfortable, flexible joint mobility. The essential experience of ginger compresses exposed the unique qualities of heat, stimulation, anti-inflammation and analgesia. Nurses could consider this therapy as part of a holistic treatment for people with osteoarthritis symptoms. Controlled research is needed with larger numbers of older people to explore further the effects of the ginger compress therapy.


Nucleolin represses transcription of the androgen receptor gene through a G-quadruplex.
The androgen receptor (AR) is a major driver of prostate cancer development and progression. Men who develop advanced prostate cancer often have long-term cancer control when treated with androgen-deprivation therapies (ADT). Still, their disease inevitably becomes resistant to ADT and progresses to castration-resistant prostate cancer (CRPC). ADT involves potent competitive AR antagonists and androgen synthesis inhibitors. Resistance to these types of treatments emerges, primarily through the maintenance of AR signaling by ligand-independent activation mechanisms. There is a need to find better ways to block AR to overcome CRPC. In the findings reported here, we demonstrate that the nuclear scaffold protein, nucleolin (NCL), suppresses the expression of AR. NCL binds to a G-rich region in the AR promoter that forms a G-quadruplex (G4) structure. Binding of NCL to this G4-element is required for NCL to suppress AR expression, specifically in AR-expressing tumor cells. Compounds that stabilize G4 structures require NCL to associate with the G4-element of the AR promoter in order to decrease AR expression. A newly discovered G4 compound that suppresses AR expression demonstrates selective killing of AR-expressing tumor cells, including CRPC lines. Our findings raise the significant possibility that G4-stabilizing drugs can be used to increase NCL transcriptional repressor activity to block AR expression in prostate cancer. Our studies contribute to a clearer understanding of the mechanisms that control AR expression, which could be exploited to overcome CRPC.


Correlations of strength, proprioception, and tactile sensation to return-to-sports readiness among patients with anterior cruciate ligament reconstruction.
Objectives: Anterior cruciate ligament reconstruction (ACLR) is the most common surgery for anterior cruciate ligament (ACL) injuries, and the relationships between patients' return to sports (RTS) readiness and different physical functions are inconclusive among patients with ACLR. This study aimed to investigate the correlations of strength, proprioception, and tactile sensation to the RTS readiness among patients with ACLR. Methods: Forty-two participants who received ACLR for at least 6 months were enrolled in this study. Their strength, proprioception, and tactile sensation were tested, and their RTS readiness was measured with the Knee Santy Athletic Return to Sports (K-STARTS) test, which consists of a psychological scale [Anterior Cruciate Ligament Return to Sports after Injury scale (ACL-RSI)] and seven functional tests. Partial correlations were used to determine their correlations while controlling for covariates (age, height, weight, and postoperative duration), and factor analysis and multivariable linear regressions were used to determine the degrees of correlation. Results: Knee extension strength was moderately correlated with K-STARTS total, ACL-RSI, and functional scores. Knee flexion strength, knee flexion and extension proprioception, and tactile sensation at the fifth metatarsal were moderately correlated with K-STARTS total and functional scores. Strength has higher levels of correlation with functional scores than proprioception. Conclusion: Rehabilitation to promote muscle strength, proprioception and tactile sensation should be performed among patients with ACLR, muscle strength has the highest priority, followed by proprioception, with tactile sensation making the least contribution.